Modeling of ligand binding to G protein coupled receptors: cannabinoid CB1, CB2 and adrenergic β2AR

  title={Modeling of ligand binding to G protein coupled receptors: cannabinoid CB1, CB2 and adrenergic $\beta$2AR},
  author={Dorota Latek and Michał Koliński and Umesh Ghoshdastider and Aleksander Dębiński and Rafal Bombolewski and Anita Płazińska and Krzysztof J{\'o}źwiak and Sławomir Filipek},
  journal={Journal of Molecular Modeling},
AbstractCannabinoid and adrenergic receptors belong to the class A (similar to rhodopsin) G protein coupled receptors. Docking of agonists and antagonists to CB1 and CB2 cannabinoid receptors revealed the importance of a centrally located rotamer toggle switch and its possible participation in the mechanism of agonist/antagonist recognition. The switch is composed of two residues, F3.36 and W6.48, located on opposite transmembrane helices TM3 and TM6 in the central part of the membranous domain… 

Ligand-specific homology modeling of human cannabinoid (CB1) receptor.

Hydrophobic Ligand Entry and Exit Pathways of the CB1 Cannabinoid Receptor

Results of mutagenesis studies evidencing that residues F1742.61 and F1772.64 are important for CB1 ligand binding are in agreement with the observations, and the most probable ligand entrance pathway into the CB1 receptor is identified.

The Hydrophobic Ligands Entry and Exit from the GPCR Binding Site-SMD and SuMD Simulations

In order to identify the most probable ligand exit pathway from lipid receptors CB1, S1P1 and LPA1 orthosteric binding sites, at least three repeats of steered molecular dynamics simulations in which ligands were pulled in various directions were performed.

Negative allosteric modulators of cannabinoid receptor 2: protein modeling, binding site identification and molecular dynamics simulations in the presence of an orthosteric agonist

Abstract Selective activation of the cannabinoid receptor subtype 2 (CB2) shows promise for treating pain, inflammation, multiple sclerosis, cancer, ischemic/reperfusion injury and osteoporosis.

Ligand discrimination during virtual screening of the CB1 cannabinoid receptor crystal structures following cross-docking and microsecond molecular dynamics simulations

The therapeutic potential of the CB1 cannabinoid receptor remains underexploited with only a few synthetic ligands on the market. The crystal structures of both the inactive and active-state CB1

Action of Molecular Switches in GPCRs - Theoretical and Experimental Studies

The structural investigations of homo- and heterodimers and higher oligomers revealed the mechanism of allosteric signal transmission and receptor activation that could lead to design highly effective and selective allosterics or ago-allosteric drugs.

Modeling, Molecular Dynamics Simulation, and Mutation Validation for Structure of Cannabinoid Receptor 2 Based on Known Crystal Structures of GPCRs

The conformational changes of CB2 upon antagonist/agonist binding were congruent with recent reports of those for other GPCRs, and a potential allosteric binding pocket adjacent to the orthosteric ligand-binding site was identified.

Computer modeling of Cannabinoid receptor type 1

A high correlation between inhibitory constant Ki of CB1 cannabinoid ligands and the ChemScore scoring function of GOLD suggests that the models of the CB1 receptors obtained could be used for docking studies and in further investigation and design of new potential, selective and active cannabinoids with the desired effects.

Identifying the structural features and diversifying the chemical domain of peripherally acting CB1 receptor antagonists using molecular modeling techniques

In the present work, pharmacophore mapping studies on diverse classes of compounds such as imidazoles, purines, pyrazines, piperazines,pyrazoles and pyrazolines have been performed to get structural insights into the CB1 receptor antagonists having peripheral activity.

Discovery of Selective Cannabinoid CB2 Receptor Agonists by High-Throughput Screening

Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1, which may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.



Dual Role of the Second Extracellular Loop of the Cannabinoid Receptor 1: Ligand Binding and Receptor Localization

The findings are consistent with a dual role for EC2 in stabilizing receptor assembly and in ligand binding and revealed that highly hydrophobic residues are required to accomplish both functions.

Structure of a β1-adrenergic G-protein-coupled receptor

G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 Å resolution crystal structure of a

Transmembrane helical domain of the cannabinoid CB1 receptor.

  • J. Shim
  • Biology, Chemistry
    Biophysical journal
  • 2009

Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations

Molecular dynamics simulations revealed different properties of the agonist 6'-GNTI and the antagonist 5'-G NTI of the κOR opioid receptor, which suggests that those two switches are interdependent.

A computational study on cannabinoid receptors and potent bioactive cannabinoid ligands: homology modeling, docking, de novo drug design and molecular dynamics analysis

Different adopting dihedral angles defined between aromatic and dithiolane rings at the active sites of the CB1 and CB2 receptors, which are adapted lead to different alkyl side chain orientations and thus, may give clues to the medicinal chemists to synthesize more selective CB ligands.

Understanding Functional Residues of the Cannabinoid CB1 Receptor for Drug Discovery

The early stages of the CB(1) receptor activation process are proposed that provide some insights into understanding molecular mechanisms of receptor activation but also are applicable for identifying new therapeutic agents by applying the validated structure-based approaches, such as virtual high throughput screening (HTS) and fragment-based approach (FBA).

Functionally Different Agonists Induce Distinct Conformations in the G Protein Coupling Domain of the β2Adrenergic Receptor*

Monitoring ligand-induced conformational changes in the G protein-coupling domain of the β2 adrenergic receptor provides new insight into the structural consequence of antagonist binding and the basis of agonism and partial agonism.

The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist

The crystal structure of the human A2A adenosine receptor is determined, in complex with a high-affinity subtype-selective antagonist, ZM241385, to 2.6 angstrom resolution and suggests a role for ZM 241385 in restricting the movement of a tryptophan residue important in the activation mechanism of the class A receptors.

Pharmacophores for ligand recognition and activation/inactivation of the cannabinoid receptors.

  • P. Reggio
  • Biology, Chemistry
    Current pharmaceutical design
  • 2003
This review focuses first on recent CB1 and CB2 SAR and on the pharmacophores that have been developed for ligand recognition at the CB1 receptor and on challenges for future SAR and pharmacophore development.

Studies of the Activation Steps Concurrent to Ligand Binding in δOR and κOR Opioid Receptors Based on Molecular Dynamics Simulations

It is proposed that, similarly as in the case of μOR (Kolinski and Filipek, TOSBJ 2008), agonists and antagonists bind to Y3.33 but only agonists are able to move deeper into the receptor binding site and to reach H6.52.